Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone

European Journal of Cancer (2014) 50, 78– 84

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Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone D. Bianchini a, D. Lorente a, A. Rodriguez-Vida b, A. Omlin a, C. Pezaro a, R. Ferraldeschi a, A. Zivi a, G. Attard a, S. Chowdhury b, J.S. de Bono a,⇑ a Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK b Guy’s and St. Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK

Available online 25 September 2013

KEYWORDS Abiraterone Enzalutamide Castration resistant prostate cancer Hormone therapy Androgen receptor targeting

Abstract Background: The new generation anti-androgen enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after enzalutamide have suggested limited activity. The antitumour activity and safety of enzalutamide after abiraterone in metastatic CRPC patients is still unknown. Patients and Methods: We retrospectively identified patients treated with docetaxel and abiraterone prior to enzalutamide to investigate the activity and safety of enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed. Results: 39 patients with metastatic CRPC were identified for this analysis (median age 70 years, range: 54–85 years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of P50% and P90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed P50% PSA decline on subsequent enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed P50% PSA decline on enzalutamide. Conclusion: Our preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.

⇑ Corresponding author: Address: Prostate Cancer Targeted Therapy Group, Royal Marsden NHS Foundation Trust, Section of Medicine, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel.: +44 2087224029. E-mail address: [email protected] (J.S. de Bono).

0959-8049/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2013.08.020

D. Bianchini et al. / European Journal of Cancer 50 (2014) 78–84

1. Introduction In the last 2 years two novel androgen-targeting agents have shown improved overall survival (OS) and quality of life for men with advanced prostate cancer [1,2]. The CYP17 inhibitor abiraterone and the novel anti-androgen enzalutamide were approved by the US Food and Drug Administration (FDA) in April 2011 and August 2012 respectively, for men with castrationresistant prostate cancer (CRPC) after docetaxel chemotherapy. Abiraterone is an irreversible and potent inhibitor of CYP17, a key enzyme for the extragonadal synthesis of androgens and estrogens. In the post-docetaxel Phase III COU-AA-301 study, abiraterone with prednisone demonstrated a 4.6-month increase in OS, with improvements in all secondary end-points, compared to placebo with prednisone [1]. Enzalutamide is a next generation non-steroidal anti-androgen that was compared to placebo in the Phase III AFFIRM trial and demonstrated a 4.8-month improvement in median OS along with superiority in all secondary efficacy measures [2]. On the COU-AA-301 trial prior enzalutamide treatment was excluded and, likewise, on the AFFIRM study prior abiraterone was not allowed. Therefore, although the individual efficacy of abiraterone and enzalutamide after docetaxel is well established, the therapeutic benefit of targeting androgen receptor (AR) signalling by sequential administration of these agents is not clear. We, and others, have reported retrospective data showing that abiraterone has limited activity when used after docetaxel and enzalutamide [3,4]. Several mechanisms of intrinsic or acquired resistance to abiraterone have been proposed in vitro and in vivo [5]. Furthermore, additional lines of therapy may allow sequential acquisition of mutations and clonal evolution that may impact the activity of subsequent treatments. The aim of this study was to retrospectively analyse the antitumour activity and safety of enzalutamide in patients previously treated with docetaxel and abiraterone.

2. Patients and methods 2.1. Eligibility Patients with metastatic CRPC that started treatment with enzalutamide within an Expanded Access Programme (EAP) at the Royal Marsden (RM) and Guy’s and St. Thomas’ (GS) NHS Foundation Trusts between June 2012 and February 2013 were retrospectively identified. Clinical data were collected from the electronic patient record. Criteria for inclusion in this study were histological diagnosis of prostate adenocarcinoma, previous docetaxel and abiraterone treatment, ongoing androgen deprivation therapy, Eastern Cooperative Group Performance Status (ECOG PS) 0–2, adequate

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haematological, hepatic and kidney function and the absence of brain metastases or a history of seizures. Patients recruited at the RM signed an informed consent allowing data collection. Local ethical approval was granted for the collection of clinical data of the patients recruited at GS. 2.2. Treatment plan and evaluations Enzalutamide was administered orally at a dose of 160 mg once daily. Baseline evaluations included medical history and physical exam, baseline imaging assessments with computed tomography (CT) and bone scans, and baseline prostate specific antigen (PSA) levels. Clinical assessments with PSA levels and blood tests including full blood count and hepatic and renal function were performed every 4 weeks. Radiological assessments were performed approximately every 6 months. Dose reductions by 25% or 50% (120 or 80 mg once daily) were allowed in case of toxicity. 2.3. Outcome measures and statistical analysis Descriptive analyses were performed to determine progression free survival (PFS) and OS, rates of PSA declines and factors associated with response and survival. PSA response was defined as a PSA decline by P50% from baseline and PSA progression as PSA rise by 25% from the nadir, both confirmed with a second PSA value at least three weeks later. Radiological response and progression were evaluated according to PCWG2 (Prostate Cancer Working Group criteria 2) and to RECIST 1.1 (Response Evaluation Criteria in Solid Tumours 1.1) [6,7] for patients with measurable disease. Clinical progression was a composite end-point that included increased disease related pain (assessed according to the 11-point numeric rating scale, with 0 representing the absence of pain and 10 representing the worst imaginable pain [8]), skeletal related events (SREs), indication for palliative radiotherapy or cancer related worsening of ECOG PS. Adverse events were graded using common terminology criteria for adverse events (CTCAE) v4.0. OS was defined as the interval between start of enzalutamide and death or date of last follow-up. PFS was defined as the interval from initiation of enzalutamide and the date of PSA, radiological or clinical progression. Time to PSA progression was defined as the interval between the initiation of enzalutamide and the date of PSA progression according to the PCWG2 criteria. Time on treatment was defined as the time interval between the date of first and last intake. Statistical analysis was performed with SPSS Statistics v20 (IBM), using the 2nd May 2013 as the cut-off date. Duration of treatment, OS, PFS and PSA progression were calculated using Kaplan-Meier estimates. Patients still on treatment or alive were censored. The

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association between PSA response on enzalutamide and OS, and of previous response to abiraterone and PFS on enzalutamide were explored using Cox regression models. The association of rates of P50% PSA response on previous abiraterone with rates of P50% PSA responses on enzalutamide was explored using binary logistic regression models. 3. Results

Table 1 Patient characteristics at initiation of abiraterone treatment. N = 39 Median Range

68 54–85

ECOG PS

0 1 2 Unknown

6 24 3 6

15.3% 61.5% 7.6% 15.3%

Gleason score

P8 =7 66 NA

21 10 7 1

53.8% 25.6% 17.9% 2.5%

Number of previous hormonal therapies

Median Range

3 1–5

Bicalutamide

Yes No

35 4

Docetaxel number of cycles

Median Range

8 1–12

PSA response to docetaxel

No Yes P30% and <50% P50% and <90% P90% NA

13 20 5

33.3% 51.3% 12.8%

9

23.1%

6 6

15.4% 15.4%

Metastatic sites

Bone Nodes Visceral

33 18 4

84.6% 46.1% 10.2%

PSA (lg/L)

Median Range

222 2.3– 997

Hb (g/dL)

Median Range

11.8 8.1– 14.7

LDH (UI/L)

Median Range

192 14.7– 508

ALP (UI/L)

Median Range

93.5 23– 1580

Albumin (g/L)

Median Range

40 31–50

3.1. Patients characteristics Between June 2012 and February 2013 a total of 39 patients were identified. The patient characteristics at abiraterone and enzalutamide initiation are described in Tables 1 and 2 respectively. The response and duration of abiraterone treatment are described in Table 3. Of the 38 patients who received abiraterone after docetaxel, 35 received abiraterone within the NHS (National Health System) and three were treated within clinical trials (two patients within the Phase I–II COU-AA003 trial and one patient within the COU-AA-BE trial). One patient participated in the Phase III COU-AA-302 trial and received abiraterone prior to docetaxel. The most common metastatic sites were bone and lymph nodes. The majority of patients had ECOG PS 1 (61.5% at the start of abiraterone and 64.1% at the start of enzalutamide) with an increased proportion of patients with ECOG PS 2 at the time of enzalutamide initiation (7.6% at the start of abiraterone and 35.8% at the start of enzalutamide). Most patients (76.9%) started enzalutamide with symptoms of disease related pain and had already received several lines of hormonal therapies and chemotherapies. A total of 14 of 39 patients (35.8%) had received also cabazitaxel as second-line chemotherapy. A total of 25 patients were already on treatment with low dose steroids (10 mg of prednisolone or 0.5 mg of dexamethasone) at start of enzalutamide and six patients required an increase in steroid dose while on treatment due to worsening fatigue and/or anorexia. Three patients had steroids prescribed during treatment with enzalutamide for the same indications. The median follow-up was 4.3 months (range: 1.0–8.2 months). 3.2. Response to enzalutamide At the time of the analysis nine patients remain on enzalutamide treatment, all of which have received at least 12 weeks of continuous treatment. The other 30 patients have discontinued enzalutamide, 28 (93.3%) due to disease progression; one because of side-effects (G3 fatigue and G1 skin rash); and one because of G3 acute kidney failure related to progressive disease diagnosed 6 days after the start of treatment and requiring discontinuation after 22 days of treatment. A total of 20 patients (20/39,

%

Age (years)

89.7% 10.3%

ECOG PS = Eastern Cooperative Oncology Group Performance Status; NA = not available; PSA = prostate specific antigen; Hb = haemoglobin; LDH = lactate dehydrogenase; ALP = alkaline phosphatase.

51.3%) discontinued enzalutamide in the first 3 months of treatment due to disease progression. Overall 16 patients (41.1%; 95% confidence interval (CI) 27.1% to 56.6%) had a confirmed PSA decline on enzalutamide of at least 30%. A confirmed PSA decline of P50% and P90% was achieved in 5/39 (12.8%; 95% CI 5.6% to 26.7%) and 1/39 (2.6%; 95% CI 0.4% to 13.2%) of patients respectively. Of the six patients with a confirmed PSA decline of at least

D. Bianchini et al. / European Journal of Cancer 50 (2014) 78–84 Table 2 Patient characteristics at initiation of enzalutamide treatment. N = 39

Table 3 Response to abiraterone treatment. %

Age (years)

Median Range

70 54–85

Type of post-abiraterone treatment

Cabazitaxel None Docetaxel retreatment Others

14 15 1 9

23

ECOG PS

0 1 2

0 25 14

0 64.2 35.8

0 1–3 4–6 7–10

9 17 10 3

23.1 43.6 25.6 7.7

Median Range

500 15– 6357

Bone Nodes Visceral

33 21 6

Hb (g/dL)

Median Range

11 8.3– 14.2

LDH (UI/L)

Median Range

225 86–876

ALP (UI/L)

Median Range

101 29– 2066

Albumin (g/L)

Median Range

37 24–48

Disease related pain

PSA (lg/L)

Metastatic sites

81

Patients

N = 39

N (%)

PSA decline on abiraterone

P30% confirmed P50% total

NE

19 (48.7%) 15 (38.4%) 15 (38.4%) 6 (15.3%) 18 (46.2%) 2 (5.1%)

Treatment duration on abiraterone (months)

Median 95% CI

6.4 3.6–9.2

Reason for discontinuation

Progression

38 (97.4%) 17 (44.7%) 35 (92.1%) 17 (44.7%) 1 (2.5%)

35.8 38.4 2.5

P50% confirmed P90% No

Radiological Biochemical

84.6 53.8 15.3

ECOG PS = Eastern Cooperative Oncology Group Performance Status; PSA = prostate specific antigen; Hb = haemoglobin; LDH = lactate dehydrogenase; ALP = alkaline phosphatase.

50%, four had received two previous lines of antiandrogen therapy and the other two received three previous anti-androgen therapies. All six patients had received previous bicalutamide, with duration of responses that ranged from 2 to 10 months. Four of the six patients were receiving steroids at the initiation of enzalutamide treatment. An additional four patients (10.3%; 95% CI 4.1% to 23.6%) had an unconfirmed PSA decline of at least 50%; in three of these patients the response was short lived and in one, treatment is still ongoing (Table 4). A waterfall plot of maximal PSA changes is shown in Fig. 1. A 50% PSA response was achieved in 4 out of 28 (14.3%; 95% CI 5.7% to 31.5%) patients with, and in 4 out of 11 (36.4%; 95% CI 15.2% to 64.6%) patients without, concomitant steroid treatment (p = 0.15). Of 23 patients with measurable disease, eight patients (34.8%; 95% CI 18.8% to 55.2%) had progressive disease, four (17.4%; 95% CI 7% to 37.1%) remained radiologically stable and one patient (4.3%; 95% CI 0.8% to

Clinical Toxicity*

NE = not evaluable; PSA = prostate specific antigen; CI = confidence interval. * One patient discontinued abiraterone due to G3 alanine aminotransferase (ALT) elevation.

21%) had a partial response. The remaining 10 patients were either discontinued due to clinical progression or were still on treatment at the time of the analysis but not yet assessed radiologically. The median duration of treatment with enzalutamide was 2.9 months (95% CI 1.7–4.0 months). 17 patients (43.6%; 95% CI 29.3% to 59%) were on treatment for at least 3 months, and four patients (10.3%; 95% CI 4.1% to 23.6%) received treatment for longer than 6 months; two of these patients are still on treatment with enzalutamide. Median OS was not reached at the time of data cut-off, with only eight events at the time of analysis. The median PFS was 2.8 months (95% CI 2.0–3.6 months) (Fig. 2). Median time to PSA progression was 2.7 months (95% CI 2.5–3 months). 3.3. Response to enzalutamide with respect to previous abiraterone therapy To evaluate whether previous response to abiraterone could predict response to enzalutamide we analysed the response to enzalutamide in abiraterone-responders (patients with a confirmed PSA decline of at least 50%) and in abiraterone-refractory patients (patients with a PSA decline of less than 50%). Of the 39 patients, 15 (38.5%; 95% CI 24.9% to 54.1%) had had at least a confirmed P50% PSA decline on abiraterone. In two patients the PSA response on abiraterone was not evaluable due to missing data. On subsequent enzalutamide treatment seven of the fifteen abiraterone-responders

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Table 4 Response to enzalutamide treatment (N = 39 unless otherwise specified). N

% (95% CI)

Current patients status (as at 02/05/2013)

Ongoing Discontinued

9 30

23.1% 76.9%

PSA decline on enzalutamide

P30% confirmed P50% total P50% confirmed P90% No NE**

16 9 5 1 22 1

41.1% (27.1–56.6) 23% (12.6–38.3) 12.8% (5.6–26.7) 2.6% (0.4–13.2) 56.4% (41–70.7) 2.6% (0.4–13.2)

Radiological response

Measurable disease PR SD PD NE

23/39 1/23 4/23 8/23 10/23

58.9% (43.4–72.9) 4.3% (0.8–21) 17.4% (7–37.1) 34.8% (18.8–55.2) 43.4% (25.6–63.2)

Treatment duration (months)

Median (95% CI) Range >3 months* >6 months

2.9 m 0.6–7.2 m 17 (9 ong) 4 (2 ong)

(1.7–4.0)

Reason for discontinuation

Disease progression Radiological Biochemical Clinical Toxicity** Other***

26 10/26 19/26 22/26 1 1

92.8% (77.4–98) 38.5% (22.4–57.5) 73.1% (53.9–86.3) 84.6% (66.5–93.9) 3.6% (0.6–17.7) 3.6% (0.6–17.7)

OS (months)

Median

NR

PFS (months)

Median Range

2.8 m 2.0–3.7

43.6% (29.3–59)

(2–3.6)

PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable; m = months; ong = ongoing; PSA = prostate specific antigen; CI = confidence interval. * Includes the four patients with a treatment duration >6 months. ** One patient was discontinued due to G1 skin rash and G3 fatigue, enzalutamide related. *** One patient discontinued enzalutamide after 22 days due to G3 acute renal failure, disease related, not enzalutamide related.

100% 80% 60% 40% 20% 0% -20% -40% -60% -80% -100%

Fig. 1. Maximum prostate specific antigen (PSA) decline on enzalutamide in all patients (PSA increase capped at 100%).

(46.7%; 95% CI 24.8% to 69.9%) achieved a confirmed P30% PSA decline while two patients (13.3%; 95% CI 3.7% to 37.9%) achieved a confirmed P50% PSA decline (Fig. 3). Of the 22 patients with a PSA decline of less than 50% on abiraterone eight patients (36.4%; 95% CI 19.7% to 57%) had a confirmed P30% PSA decline on enzalutamide with two patients (9.1%; 95%

Fig. 2. Progression free survival on enzalutamide.

CI 2.5% to 27.8%) reaching a confirmed P50% PSA decline (Fig. 4); one of these biochemical responses is still ongoing. There was no association between previous P50% PSA response to abiraterone and P50% PSA response to enzalutamide (p = 0.186). There was no

D. Bianchini et al. / European Journal of Cancer 50 (2014) 78–84 100% 80% 60% 40% 20% 0% -20% -40% -60% -80% -100%

Fig. 3. Maximum prostate specific antigen (PSA) decline on enzalutamide in patients with >50% PSA decline on previous abiraterone (PSA increase capped at 100%).

100% 80% 60% 40% 20% 0% -20% -40% -60% -80% -100%

Fig. 4. Maximum prostate specific antigen (PSA) decline on enzalutamide in patients with <50% PSA decline on previous abiraterone (PSA increase capped at 100%).

statistically significant difference in PFS on enzalutamide in previous abiraterone-responders compared with non-responders (2.99 versus 2.27 months, p = 0.76). 3.4. Safety The main side-effect of enzalutamide treatment reported in 64.1% of patients was fatigue (all grades). In the majority of cases (38.4%) fatigue was of moderate severity (G2), but fatigue was severe (G3) in one patient (2.5%) and led to permanent treatment discontinuation. G2/3 fatigue required temporary treatment interruption in five patients; in two additional patients G2 fatigue was managed with a dose reduction by 25% and 50% respectively. Other common side-effects included anorexia (20.5%, all grades), nausea (10.2%, all grades) and depressive mood (7.6%, all grades). No seizures were reported. 4. Discussion With the successful development and approval of cabazitaxel, abiraterone and enzalutamide physicians

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are facing the difficult task of selecting the optimal sequence for patients with CRPC progressing post-docetaxel. At present, no clinical or biological factors have been shown to predict response to these agents and treatment choices are based on availability, patient and clinician preferences and performance status or comorbidities. This retrospective study provides for the first time preliminary data on the activity of enzalutamide in advanced and heavily pre-treated CRPC patients previously treated with abiraterone. In these patients, enzalutamide resulted in confirmed P50% PSA declines in 12.8% of patients. The median duration of treatment was 2.9 months (95% CI 1.7–4). In patients deemed abiraterone-refractory on the basis of <50% PSA decline, we observed P30% and P50% PSA declines on enzalutamide in eight (36.3%) and three patients (13.6%) respectively. Similarly, a recently presented phase I/II study of ARN-509, a novel AR antagonist with a similar mechanism of action to enzalutamide, reported a considerably lower 50% PSA decline rate in abiraterone pre-treated patients (4 out of 14, 29%), than in abiraterone-naı¨ve patients (22 out of 25, 88%) [9]. These data indicate some cross-resistance between these novel agents. Our dataset was limited by the small patient population as well as the retrospective nature of the analysis. Despite these limitations, we observed lower rates of PSA declines and shorter durations of enzalutamide treatment in the post-docetaxel and post-abiraterone setting compared with the PSA response rate of 54% and median treatment duration of 8.3 months reported in the AFFIRM study in abiraterone-naı¨ve patients [2] and the even higher response rates seen in docetaxel naı¨ve patients. These differences may have been influenced by the advanced disease stage in our population (ECOG PS 2 in 8.5% of patients enrolled in AFFIRM versus 35.8% in our cohort) resulting in reduced physical tolerance and worse outcomes. Nevertheless, any mechanisms of cross-resistance between abiraterone and enzalutamide appear incomplete and included a 99.7% confirmed PSA decline and long-lasting response to enzalutamide in one patient whose disease had proved refractory to abiraterone. Similarly, our recently published data on the activity of abiraterone in 38 post-docetaxel and post-enzalutamide patients showed confirmed P50% PSA declines in only 8% of patients and a median PFS of 2.7 months (95% CI: 2.3–4.1) [4], which was inferior to the PSA response rate of 29% and median treatment duration of 8 months for enzalutamide-naı¨ve patients reported in the COU-AA-301 trial [1]. Preclinical data have proposed several possible mechanisms of resistance to abiraterone and enzalutamide, including AR mutations [5,10], constitutively active AR splice variants [11], AR activation by concomitant

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glucocorticoid use [12,13] and activation of AR-independent signalling pathways such as the phosphatidylinositide 3-kinase (PI3K) - protein kinase B (Akt) mammalian target of rapamycin (mTOR) pathway [14]. Several mechanisms of resistance are likely in different patients, and perhaps even in the same patient, due to clonal heterogeneity as a result of disease clonal evolution induced by therapeutic selective pressure. Overall, enzalutamide remained a safe and relatively well tolerated treatment in an advanced patient population. In the absence of better clinical or biological predictive factors of treatment response, the activity of enzalutamide after docetaxel and abiraterone may represent a valid treatment option for the advanced prostate cancer patient. In conclusion, enzalutamide has modest antitumour activity in advanced-stage CRPC patients when used after docetaxel and abiraterone. Larger prospective studies are now needed to provide further data regarding optimal treatment sequencing and the potential benefits of combing abiraterone and enzalutamide. Conflict of interest statement Disclosure: Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. C.P. received lecture fees from Sanofi-Aventis and travel support from Sanofi-Aventis and Janssen-Cilag. G.A. received consulting fees and travel support from Janssen-Cilag, Veridex, Roche/Ventana and Millennium Pharmaceuticals, lecture fees from Janssen-Cilag, Ipsen, Takeda and Sanofi-Aventis, and grant support from AstraZeneca and Genentech. G.A. is on The ICR rewards to inventors list of abiraterone acetate. S.C. received honoraria and is a member of the advisory boards of Janssen-Cilag and Sanofi-Aventis. J.S.d.B. received consulting fees from Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, and Takeda, and grant support from AstraZeneca and Genentech. Funding: D.B., D.L., C.P., A.O., R.F., A.Z. and J.S.d.B are employees of the Section of Medicine that is supported by a Cancer Research UK programme grant and an Experimental Cancer Medical Centre

(ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). A Cancer Research UK Clinician Scientist Fellowship supports G.A. The authors acknowledge NHS funding to the Royal Marsden NIHR Biomedical Research Centre. A.O. is recipient of a 2-year bursary from the Swiss Cancer League (No. BIL KLS-02592-02-2010). References [1] De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Eng J Med 2011;364(21):1995–2005. [2] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Eng J Med 2012;367(13):1187–97. [3] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013;24(7):1807–12. [4] Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013;24(7):1802–7. [5] Ferraldeschi R, Sharifi N, Auchus RJ, Attard G. Molecular pathways: inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res 2013;19(13):3353–9. [6] Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26(7):1148–59. [7] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–47. [8] McCaffery M, Beebe A. Pain: clinical manual for nursing practice. Baltimore: V.V. Mosby Company; 1993. [9] Rathkopf DE, Antonarakis ES, Shore ND, et al. ARN-509 in men with metastatic castration-resistant prostate cancer (mCRPC). ASCO Meet Abstr 2013;31(6 Suppl.):48. [10] Zhao XY, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 2000;6(6):703–6. [11] Li Y, Chan SC, Brand LJ, Hwang TH, et al. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 2013;73(2): 483–9. [12] Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 2013;73(5):1570–80. [13] Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012;72(9):2176–82. [14] Carver BS, Chapinski C, Wongvipat J, Hieronymus H, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011;19(5):575–86.